One solution to drug delivery and/or bioavailability issues in pharmaceutical development is converting known drugs to prodrugs. Typically, in a prodrug, a polar functional group (e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.) is masked by a promoiety, which is labile under physiological conditions. Accordingly, prodrugs are usually transported through hydrophobic biological barriers such as membranes and typically possess superior physicochemical properties in comparison to the parent drug.
Pharmacologically effective prodrugs are non-toxic and are preferably selectively cleaved at the locus of drug action. Ideally, cleavage of the promoiety occurs rapidly and quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety).
The acyloxyalkoxycarbonyl functionality is an example of a promoiety that may be used to modulate the physiochemical properties of pharmaceuticals (Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S. Pat. No. 5,733,907; Alexander et al., U.S. Pat. No. 4,426,391). Typically, 1-(acyloxy)-alkyl derivatives of pharmaceuticals possess superior bioavailability, are usually less irritating to topical and gastric mucosal membranes and more permeable through such membranes, when compared to the parent drugs.
However, although 1-(acyloxy)-alkyl ester derivatives of alcohols and 1-(acyloxy)-alkyl carbamate derivatives of amines have been frequently used to mask these polar functional groups in pharmaceuticals, existing synthetic methods for preparing these desirable prodrugs are inadequate. Existing methods for synthesis of acyloxyalkyl esters and carbamates are typically multi-step routes that utilize unstable intermediates and/or toxic compounds or salts and are difficult to perform on a process scale (Alexander, U.S. Pat. No. 4,760,057; Lund, U.S. Pat. No. 5,401,868; Alexander, U.S. Pat. No. 4,916,230; Saari et al., European Patent 0416689B1).
Although, 1-acyl-alkyl derivatives of drugs are known in the art (Sakamoto et al, Chem. Pharm. Bull. 1985, 33, 4870-4877; Hayashibe et al, International Publication No. WO 00/59913; Hartmann et al, International Publication No. WO 96/40156; Bal-Tembe et al, Bioorg. Med. Chem. 1997, 5, 1381-1387; Dow et al, European Patent Application No. EP1088819; Hong et al, Eur. J. Cancer Clin. Oncol. 1983, 19, 1105-1112; Ogata, K. Jpn. Kokai Tokkyo Koho JP 2001002690; Ashton et al, International Publication No. WO 95/20567; and Charpiot et al, Bioorg. Med. Chem. 2001, 9, 1793-1805) these compounds have not been converted to 1-(acyloxy)-alkyl prodrug derivatives. Accordingly, there is a need for a new synthesis of 1-(acyloxy)-alkyl derivatives that proceeds rapidly and efficiently, without the use of activated intermediates and/or toxic compounds, which is amenable to scale-up and proceeds through readily accessible synthetic precursors. Further, there is also a need for 1-acyl-alkyl derivatives, which may serve as synthetic precursors to 1-(acyloxy)-alkyl derivatives.